Investigation of molecular etiology of Snijders Block-Campeau syndrome.
Just recently discovered, SBCS significantly diminishes the quality of life for hundreds of families worldwide. To this point, the investigation into the molecular etiology of SBCS has only just begun. Our tasks concerning SBCS include the following:
Assessment of SBCS distribution among the Ukrainian populations:
To date, there are no reports of SBCS cases in Ukraine. However, it is highly unlikely that such a syndrome is absent from Ukrainian populations. Hence, we aim to conduct systematic research to describe the cases of SBCS in Ukraine and to understand which particular variants of CHD3 exist in the population or arise de novo. Obtaining this knowledge is crucial for raising social awareness about SBCS, as well as improving the awareness of healthcare providers and simplifying the diagnostics of SBCS in Ukraine.
Creation of models for the experimental investigation of SBCS:
According to the OMA Orthology database, CHD3 orthologues are present in various metazoans. However, experimental investigations of the CHD3 role in neurodevelopment are lacking. Scarce reports suggest that in Drosophila melanogaster, the CHD3 orthologue is not crucially important, while in Caenorhabditis elegans, it might be involved in neuronal differentiation. In mice, deletion of the CHD3 orthologue seems to lead to partial embryonic lethality. Nevertheless, none of these studies have described behavioral tests of CHD3-deficient animals. Thus, the model to study CHD3 function remains unclear. To address this, we aim to create an animal model that allows for the experimental investigation of CHD3 functions.
Development of gene-therapeutic approaches for SBCS:
With a reliable model object, we would be able to test different approaches for the gene therapy of SBCS. Given that the size of the gene is larger than the average packaging capacity of AAV-based vectors, gene therapy for SBCS might pose a serious challenge. However, we currently see several promising avenues for the treatment of SBCS.
Novel insights into the molecular mechanisms underlying Angelman syndrome
AS is one of the best-studied neurodevelopmental disorders. However, we believe that our understanding of AS can still be expanded by studying the evolution of UBE3A. Notably, orthologues of UBE3A exist in numerous metazoans; investigating such orthologues is important to understand how UBE3A became significant over the course of evolution. At the same time, it is known that several UBE3A paralogues exist within the human genome, but our knowledge of their functions is limited. Thus, our aims include:
1) Comparative study of UBE3A orthologues from different metazoans:
Reliable cellular and murine models exist that allow the investigation of UBE3A functions in vivo and in vitro. We plan to use several such systems to analyze the properties of a selected set of UBE3A orthologues representing different evolutionary lineages of metazoans. Integrating the experimental results with comparisons of amino acid sequences and phylogenetic modeling will allow us to shed new light on the evolutionary history of UBE3A in metazoans.
2) Functional assessment of human UBE3A paralogues:
The human genome contains several additional genes coding for ubiquitin ligases. So far, the exact functions of these genes remain poorly understood. Hence, we aim to investigate their functions in more detail, as such genes might be alternative tools for gene-therapeutic approaches for AS.
Experimental evolution of AAV-based vectors.
Creation of a library of soil bacteria from extreme anthropogenic environments as source for novel bioactive secondary metabolites.
Our hypothesis is that extreme anthropogenic environments promote complex microbial interactions, forcing the inhabiting bacteria to develop more varied arsenals of secondary metabolites. With its post-industrial Soviet legacy, Ukraine is rich in such extreme anthropogenic environments, which we aim to explore. Hence, we set our goal to isolate as much as possible of such bacteria coming from the phyla Actinomycetota (actinomycetes), Bacillota (bacilli), and Myxococcota (myxobacteria), identify them on species level, sequence the genomes of such bacteria, and apply our experience in search for novel antibiotics, antifungals, and putative anticancer secondary metabolites.